tbuckley/cabot-search huggingface dataset:
An open-label, multicenter, phase II study of RC48-ADC combined with radiotherapy, PD-1/PD-L1 inhibitor sequential GM-CSF and IL-2 for salvage therapy in patients with HER2-expressing advanced solid tumors(PRaG3.0).
Authors: Meiling Xu, Yuehong Kong, Pengfei Xing, Rongzheng Chen, Yifu Ma, Chanchan Shan, Liyuan Zhang
Journal: Journal of Clinical Oncology (2022)

e14565 Background: The development of anticancer therapy tends to focusing on pan-cancer analysis, targeted therapy and immunotherapy with the advance of molecular and tumor microenvironment. Radiotherapy produces an immunomodulatory effect that may act synergistically with PD-1/PD-L1 inhibitor in multiple malignancies. Previous phase II trial showed HFRT/SBRT combined with PD-1 inhibitor and GM-CSF (PRaG regimen) has obtained promising results(Yuehong Kong et al. ASTRO 2021). RC48-ADC is a novel HER2-targeting antibody-drug conjugate (ADC). Preclinical studies indicated that ADC elicit immunogenic cell death and selectively radiosensitize to tumours. RC48-ADC combined with HFRT, PD-1/PD-L1 inhibitor sequential GM-CSF and IL-2 (PRaG3.0 regimen) could further improve the synergistic antitumor effects, this precise combination therapy paradigm provides an exploratory path for the treatment of pan-cancer. An exploratory phase II, open-label, multi-centre, single-arm study was conducted to evaluate the initial clinical efficacy and safety of PRaG3.0 regimen for treatment of HER2-expressing advanced solid tumors. Methods: Participants with advanced, confirmed HER2-expressing(IHC3+, 2+ or 1+) solid tumors that had progressed after the standard of care or intolerance were enrolled. In the cycle, those received RC48-ADC(2.0 mg/kg d1, every 3 weeks), then HFRT (2-3 doses of 5-8Gy) was delivered for one metastatic lesion every other day, followed by GM-CSF(200 μg d3-7), sequential IL-2(2million IU d8-12), and PD-1/PD-L1 inhibitor was dosing within one week after completion of HFRT. After RC48-ADC combined with PD-1/PD-L1 inhibitor sequential GM-CSF and IL-2 for at least 6 cycles, then maintenance with PD-1/PD-L1 inhibitor was administered until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR). This trial is registered with ClinicalTrials.gov, number NCT05115500. Results: With the cutoff date of 11 February 2022, a total of 8 patients were enrolled. Among 6 patients who had at least one tumor assessment, involved gastric cancer(3/6), breast cancer(1/6), cervical cancer(1/6), pancreatic cancer(1/6). The ORR was 66.7% (4/6) and disease control rate (DCR) was 83.3%(5/6). One cervical cancer and one pancreatic cancer achieved complete remission. The most common treatment-related adverse events (TRAEs) were alopecia (37.5%), fatigue (25%) and hepatic damage(12.5%). No Grade 3 and higher adverse events occurred. Conclusions: The PRaG3.0 regimen manifested manageable safety profile and encouraging efficacy. So PRaG3.0 regimen is considered as a promising salvage treatment for patients with HER2-expressing advanced solid tumors. And the conclusion should be validated in more patients subsequently. Clinical trial information: NCT05115500.
Multi-institutional randomized phase 3 trial comparing cancer stem cell-targeted versus physician-choice treatments in patients with recurrent high-grade gliomas (NCT03632135).
Authors: Tulika Ranjan, Soma Sengupta, Michael J. Glantz, Christine Lu-Emerson, Richard M. Green, Candace M. Howard, Alexander Yu, Ricky Chen, Rekha T. Chaudhary, Dawit Aregawi, Jon Glass, Aaron Gerald Mammoser, Hugh Moulding, Steven Jubelirer, Jason Schroeder, Mark Daniel Anderson, Seth T. Lirette, Anthony Alberico, Jagan Valluri, Pier Paolo Claudio
Journal: Journal of Clinical Oncology (2022)

2028 Background: Clinical outcomes in patients with recurrent high-grade glioma (HGG) remain poor. Cancer stem cells (CSCs) have been implicated in metastasis, treatment resistance and recurrence of HHGs. We have shown in several clinical studies that anti-CSC-directed therapy selected by ChemoID assay provides benefits in many cancer types; however, this is the first report of a randomized clinical trial evaluating whether CSC-targeted cytotoxic agents selected by ChemoID assay-guided therapy improves survival in patients with recurrent HGG. Methods: In this parallel-group, randomized, phase-3 clinical trial, patients at 13 clinical sites in the USA with grade-III/IV recurrent glioma (2016 WHO guidelines) were randomized 1:1 to either ChemoID assay-guided therapy or physician-choice therapy, and then treated and followed until unacceptable toxic effects, hospice, or death. The primary endpoint was overall survival (OS). Results: Combined median follow-up was 9 months. Median OS (mOS) was 12.5 months (95% CI, 10.2-14.7) in the ChemoID assay-guided group vs 9 months (95% CI, 4.2-13.8) in the physician-choice group (log-rank P =.010). Risk of death was significantly lower in the ChemoID assay group (HR = 0.44; 95% CI, 0.24-0.81; P =.008). Median progression free survival (PFS) was 10.1 vs 3.5 months (95% CI, 4.8-15.4 vs 1.9-5.1) (HR, 0.25; 95% CI, 0.14-0.44; P &lt;.001). Conclusions: Primary endpoint was met in this randomized clinical trial. The mOS was 3.5 months longer in the ChemoID assay-guided group vs the physician-choice group. Clinical trial information: NCT03632135.
Metastatic patterns plus clinical and molecular characteristics of <i>ROS1</i> aberrations in non-small cell lung cancer patients without rearrangements.
Authors: Moritz Glaser, Cornelia von Levetzow, Sebastian Yves Friedrich Michels, Lucia Nogova, Marianna Katzenmeier, Claudia Wompner, Jaqueline Schmitz, Elisabeth Bitter, Inken Terjung, Elke Passmann, Diana Schaufler, Anna Eisert, Rieke Nila Fischer, Richard Riedel, Jan-Phillip Weber, Sabine Hahne, Sabine Merkelbach-Bruse, Reinhard Büttner, Juergen Wolf, Matthias Scheffler
Journal: Journal of Clinical Oncology (2022)

e21117 Background: Fusions in the ROS1 proto-oncogene are among the best treatable genetic aberrations in Non-small cell lung cancer (NSCLC). Besides the occurrence of solvent-front mutations (SFM) in acquired resistance to targeted therapy, little is known about ROS1 aberrations other than fusions. We analyzed molecular and clinical characteristics and metastatic patterns of ROS1 mutations in NSCLC patients without activating ROS1 fusions or SFMs. Methods: Next-generation sequencing (NGS) was performed on tissue samples from NSCLC patients within the National Network Genomic Medicine (nNGM). Patients with activating ROS1 fusions detected by fluorescence in-situ hybridization (FISH) were excluded. Staging and restaging procedures were performed following local standards from each partner. We analyzed the mutations’ characteristics, co-occurring mutations and metastatic patterns. Results: Of 8072 patients analyzed by NGS between 2018 and 2021, 118 (1.5%) patients harbored ROS1 mutations. Most patients were male (76.3%) and had adenocarcinoma histology (57.6%). The median age at diagnosis amounted to 68 years. Nearly all of the patients (96.5%) had a smoking history, amassing 40 pack-years on average. Besides TP53 mutations (61.0%), KRAS (25.4%), EGFR (7.6%), PIK3CA and FGFR1-4 mutations (5.9% each) co-occurred most frequently. In 12 (10.2%) patients, ROS1 mutation was the only detected aberration. The majority (59.3%) of patients had UICC stage IV whereby 27.2% of patients featured Stage III; about 7% fall upon stage I and II. The metastatic pattern of all stage IV patients shows that 22.9% of metastasis is allotted to cerebral, 12.5% to lung, 16.7% to subdiaphragmatic, 14.9% to bone and 6.3% to skin metastasis. Thereby, the patients’ subgroup with mutually exclusive ROS1 mutations (10.2%) resembles this trend: about a half of these patients had UICC stage IV, too, and the metastasis distribution featured similar characteristics. Conclusions: The cohort contrasts the clinical characteristics of patients with ROS1 fusion regarding sex, age, and histology. This evidence implies a basic clinical impact exerted by this molecular subtype. We warrant further research on the detected mutations to characterize the biological impact and the potential to act as a drug target.
Real-life experience of rare hepatoid adenocarcinomas of the lung: A large retrospective french cohort.
Authors: Thomas Favé, Gilles Quere, Gilles Robinet, Hélène Babey, Emmanuelle Renaud, Estelle Dhamelincourt, Jessica Nguyen, Arnaud Simaki Amah, Victor Basse, Renaud Descourt, Margaux Geier
Journal: Journal of Clinical Oncology (2022)

e21091 Background: Hepatoid adenocarcinoma of the lung (HAL) is a rare subtype of lung cancer exhibiting common histological features with hepatocellular carcinomas (HCC). Therapeutic landscape is currently similar to lung adenocarcinoma standards. We report here the largest descriptive cohort of HAL with focus on (chemo)-immunotherapy (CT-IO) efficacy. Methods: In this single-center retrospective observational study, we selected all consecutive cases of HAL patients from January 2013 to January 2022. Eligible patients had primary lung tumor with positive immunohistochemical hepatocyte marker. HCC was eliminated with liver imaging. We provide a descriptive analysis of HAL population and describe our therapeutic experience. Results: A total of 21 patients were included. Main characteristics at diagnosis were: median age of 63 years [41-81], 80,9% of males, with 76,2% of PS 0-1. All patients had smoking history, with 8 active smokers. Twenty patients (95,2%) had stage IV disease. Median number of metastatic sites was 2; 7 (33,3%) patients had brain metastases. PD-L1 status was &lt; 1% (n = 10), 1-5% (n = 2), ≥50% (n = 5), unknown (n = 4). Six (28,6%) patients harbored KRAS mutation: G12C (n = 4), G60D (n = 1), G12V (n = 1). One patient had Lynch syndrome with MMR deficiency. Median follow-up was 5 months. Median overall survival (mOS) since diagnosis achieved 9 months (95% CI, 3 to 21). Early palliative care concerned 6 patients. Five patients received first-line CT-IO. Best response was: partial response (n = 3), stable disease (n = 1), progressive disease (n = 1). One patient treated with first-line pembrolizumab achieved stable disease. Four patients received second-line IO but experienced early progressive disease. Conclusions: Our results highlighted the aggressive metastatic profile of HAL accounting for the poor mOS of 9 months. Patients could benefit from upfront CT-IO but further studies are warranted to confirm it.
Correlation of the oncotype DX breast recurrence score and the ki-67 IHC MIB-1 pharmDX score in HR+, HER2-, node-positive early breast cancer.
Authors: Michael Crager, Sameera R. Wijayawardana, Aaron M. Gruver, Andrea Blacklock, Frederick L Baehner, Christy Russell, Francisco J. Sapunar
Journal: Journal of Clinical Oncology (2022)

e12556 Background: In monarchE, abemaciclib, an oral CDK4/6 inhibitor, when combined with endocrine therapy (ET, tamoxifen or aromatase inhibitor) significantly improved invasive disease-free survival in patients with HR+, HER2-, node positive early breast cancer (EBC) at high risk of early recurrence and Ki-67 score ≥20%. The US FDA subsequently approved the Ki-67 IHC MIB-1 pharmDx assay (Dako Omnis) as a companion diagnostic. The Oncotype DX Breast Recurrence Score assay has similarly been validated in HR+, HER2- invasive breast cancers (IBC) to predict chemotherapy benefit and risk of distant recurrence at 10 years regardless of node status. While several studies have previously shown a relationship between Ki-67 IHC assays and RS, this relationship has not yet been evaluated using the standardized Ki-67 assay established for monarchE. The primary objective was to estimate the correlation between the Recurrence Score (RS) result and the monarchE Ki-67 IHC score using prospectively collected node positive, HR+, HER2- IBC specimens. A secondary objective assessed the proportion of node positive, HR+ patients with RS 26-100 that have Ki-67 IHC score &gt;20%. Methods: IBC samples were acquired from Exact Sciences following an IRB-approved protocol. Samples from US patients with HR+, HER2- IBC, 1-3 positive lymph nodes (N1) with available RS result and sufficient tumor content were eligible. After collection of 275 samples with all RS results eligible (“All- RS pool”), 36 more samples with RS 26-100 were collected with high RS (HI RS only”). Unstained tissue sections were subsequently sent to Agilent Technologies for Ki-67 IHC using the monarchE assay. The consensus diagnostic category (positive/negative) and an average of the two closest % positivity scores were used for the final dataset. Spearman rank correlation and cross tabulations of RS result with % Ki-67 were performed according to the predetermined statistical analysis plan. Results: 311 samples were collected, 1 with a null Ki-67 result. Twelve samples had a pathology report with node negative assessment, leaving 298 samples and 262 in the All-RS pool. The rank correlation between % Ki-67 and RS result in the all-RS pool in the node positive population was 0.396 (95% CI 0.288 – 0.493). Cross-tabulations of the Ki-67 diagnostic category (&lt; 20% vs ≥ 20%) against the RS were made using all available data (All-RS pool+HI RS only). Among 218 samples with RS 0-25, 164 (75%) had Ki-67 &lt;20% and 54 (25%) had Ki-67 ≥20%. Among 80 samples with RS 26-100, 57 (71%) had Ki-67 ≥20% and 23 (29%) had Ki-67 &lt;20%. Conclusions: A moderately positive correlation between the Oncotype DX Breast Recurrence Score result and the Ki-67 IHC MIB-1 pharmDx Score in HR+, HER2- node positive EBC was observed in the All-RS pool. These findings are consistent with prior studies.
Medical assistance in dying (MAiD) in patients with cancer.
Authors: Sara Moore, Chloe Thabet, Paul Wheatley-Price
Journal: Journal of Clinical Oncology (2022)

12028 Background: Medical assistance in dying (MAiD) was legalized in Canada in 2016. Cancer accounts for 60-70% of MAiD cases, though little is known about the demographic profile, cancer diagnoses, and treatments received in patients with cancer who pursue MAiD. We reviewed all patients with cancer who underwent MAiD through a large regional MAiD program, in order to better understand this population and identify gaps in the current system of care delivery. Methods: All patients with cancer who received MAiD through the Champlain Regional MAiD Network (CRMN) from June 1 2016 – November 30 2020 were reviewed. The CRMN provides the majority of MAiD services covering a population of 1.3 million in Eastern Ontario. Baseline demographic factors, diagnostic information, and treatment details were collected by retrospective review. The primary endpoint was the proportion of patients with an oncology consultation prior to MAiD. Results: During the study period, 255 patients with cancer underwent MAiD. Baseline characteristics included: median age at death 71 (range 31-100), 51% male, 56% married/common-law. The most prevalent solid tumors were gastrointestinal [GI] (n = 77, 30%), lung (n = 47, 18%), and genitourinary [GU] (n = 35, 14%). Most patients (n = 201, 79%) had metastatic disease at the time of MAiD. Of those without metastatic disease at time of death, common tumor sites included central nervous system (42%) and head and neck (23%). The majority of patients (n = 229, 89%) had seen an oncology specialist prior to MAiD; 226 (88%) had seen a systemic oncologist (medical, hematologic, or gynecologic oncologist), and 189 (69%) a radiation oncologist. Seventy-three percent of patients were followed by a systemic oncologist within 90 days of MAiD, and 44% within 30 days of MAiD. At least one line of systemic therapy was received by 159 (62%) patients, 138 (54%) received radiotherapy, and 61 (24%) best supportive care alone. Median time from last systemic therapy to MAiD was 85 days, and from last radiation therapy to MAiD was 137 days. Palliative care assessed at least 213 patients (84% [8% unknown]). Common reasons for pursuing MAiD included disease-related symptoms (33%), fear of future suffering or disability (19%), and ability to control the time and manner of death (17%). Among 26 patients who had not seen an oncologist, median age was 84 (range 61-100), 77% male, 42% GI primary / 19% GU / 15% lung. Most had seen a palliative care specialist (n = 23, 88%), and in the remaining 3 patients palliative care involvement was unknown. Conclusions: MAiD is a relatively new option for patients with cancer in Canada. The vast majority of patients with cancer who pursue MAiD are diagnosed with advanced/incurable disease, and most have met with an oncology specialist. As cancer treatments become more effective and more tolerable, collaboration between oncologists and MAiD providers is required to ensure patients are well informed of treatment options prior to MAiD.
Methylated DNA markers discriminate ovarian cancer from benign tissue in BRCA carriers.
Authors: Jessica Weng, Jamie Nadine Bakkum-Gamez, Seth Slettedahl, Douglas W. Mahoney, Xiaoming Cao, Patrick H. Foote, Kelli Burger, Calise K. Berger, Maria O'Connell, Jacquelyn R. Arndt, Karen A. Doering, Mark E. Sherman, William R. Taylor, Longwen Chen, Fergus Couch, John B. Kisiel, Jewel Samadder
Journal: Journal of Clinical Oncology (2022)

e17610 Background: Methylated DNA markers (MDMs) associated with sporadic ovarian cancer (OC) are detected in plasma from patients with treatment naïve tumors, but not cancer-free controls. To assess potential benefits to patients at risk for hereditary OC, the aim of this study was to measure the performance of validated sporadic OC MDMs in OC and benign ovarian tissue (BOT), surgically obtained from germline BRCA1 or BRCA2 ( BRCA1/2) mutation carriers. Methods: BRCA1/2 carriers with OC and BRCA1/2 carriers who had undergone risk-reducing salpingo-oophorectomy (SO) were identified at a comprehensive cancer center. BRCA1/2 carriers in both OC and BOT groups were balanced on age and year of surgery with non- BRCA carriers with sporadic OC or benign indications for SO. OC and BOT formalin fixed paraffin embedded (FFPE) tissues were macrodissected following pathologist selection of representative sites; DNA was extracted, and bisulfite converted. 15 OC MDMs ( GDF6, IFFO1, MAX.chr1.147790358, MAX.chr6.10382190, MAX.chr11.14926602, C2CD4D, PDRM14, NCOR2, SKI, DSCR6, SIM2, PALLD, CDO1, GPRIN1, BCAT1) previously identified in sporadic OC were assayed by quantitative methylation specific PCR, normalized by β-actin, by blinded personnel. Areas under the receiver operating characteristic curve (AUC) were generated for each MDM to assess discrimination of OC from benign tissue and compared between BRCA1/2 and sporadic (non- BRCA) patients, using a z-test. Results: Among BRCA1/2 carriers, there were 48 OC ( BRCA-OC) and 48 BOT ( BRCA-BOT); among non- BRCA, we matched 48 OC (Sporadic-OC) and 48 BOT (non- BRCA-BOT). The median AUC for OC MDM discriminated between OC and BOT with AUCs in BRCA1/2 carriers was 0.87, (IQR, 0.83-0.93). Sporadic-OC vs non- BRCA-BOT median AUC was 0.88 (IQR, 0.83-0.92). AUCs were not significantly different for each MDM when stratified by BRCA or sporadic status. MDMs with an AUC of ≥0.9 in either group are shown (Table). Conclusions: OC MDMs identified and validated in sporadic OC are highly discriminant for OC from BOT in DNA extracted from tissues of people who carry a BRCA1/2 mutation. Testing the performance of these OC MDMs in plasma from BRCA1/2 carriers with and without OC may be of clinical value for high-risk patients and inform multi-cancer early detection testing strategies.[Table: see text]
Effectiveness of nationwide insurance coverage for next-generation sequencing in advanced colorectal cancer: A real-world data study.
Authors: Sun-Kyeong Park, Dong-Won Kang, Ye Lee Yu, Yongjun Cha, Sokbom Kang
Journal: Journal of Clinical Oncology (2022)

3602 Background: Next-generation sequencing (NGS) has been covered by Korean national health insurance since March 2017 for patients with advanced colorectal cancer (CRC). We explored the clinical and socioeconomic impact of NGS compared with that of a single gene test (SGT) alone. Methods: From the nationwide database, we identified patients who 1) are diagnosed with advanced CRC classified as a distant disease using Summary Stage between March 1, 2017, and December 31, 2018; 2) had NGS or SGT within 2 months after diagnosis of advanced CRC. Multivariate logistic regression with covariates including age, sex, Charlson comorbidity index, insurance type, year of diagnosis, and region and type of hospital with the initial diagnosis was conducted to identify factors affecting the performance of NGS. We conducted 1:3 propensity score matching to minimize the impact of confounding factors. The median overall survival and the adjusted hazard ratio (aHR) were estimated using the Kaplan-Meier method and the Cox proportional hazard model, respectively. We calculated the total medical cost, and per patient per year (PPPY) cost adjusted for the survival period. Results: Among 5,029 patients with advanced CRC, 655 patients were identified as NGS group and 1,995 as SGT group after matching. Old age, low household income, rural location, and non-tertiary hospital were all characteristics that reduced the likelihood of obtaining an NGS test. The NGS group showed significantly favorable survival compared to the SGT group (median survival 29.2 vs. 24.9 months, P =.031; adjusted hazard ratio [HR] 0.86, P =.034). The total medical cost was lower in the NGS group ($55,445) than the SGT group ($57,989), and the PPPY cost was also lower in the NGS group ($44,879 and $49,734, respectively). Conclusions: We found that some socioeconomic factors such as age, insurance type, region, and hospital type may hamper the implementation of NGS. Also, lowering the barrier of NGS tests by reimbursing NGS in a specific clinical setting may have survival and cost-benefit in patients with advanced CRC.